The nationwide claims data lake for sleep apnoea (ALASKA)-real-life data for understanding and increasing obstructive sleep apnea (OSA) quality of care study-investigated long-term continuous positive airway pressure (CPAP) termination rates, focusing on the contribution of comorbidities. The French national health insurance reimbursement system data for new CPAP users aged ≥18 years were analyzed. Innovative algorithms were used to determine the presence of specific comorbidities (hypertension, diabetes and chronic obstructive pulmonary disease (COPD)). Therapy termination was defined as cessation of CPAP reimbursements. A total of 480,000 patients were included (mean age 59.3 ± 13.6 years, 65.4% male). An amount of 50.7, 24.4 and 4.3% of patients, respectively, had hypertension, diabetes and COPD. Overall CPAP termination rates after 1, 2 and 3 years were 23.1, 37.1 and 47.7%, respectively. On multivariable analysis, age categories, female sex (1.09 (1.08-1.10) and COPD (1.12 (1.10-1.13)) and diabetes (1.18 (1.16-1.19)) were significantly associated with higher CPAP termination risk; patients with hypertension were more likely to continue using CPAP (hazard ratio 0.96 (95% confidence interval 0.95-0.97)). Therapy termination rates were highest in younger or older patients with ≥1 comorbidity. Comorbidities have an important influence on long-term CPAP continuation in patients with OSA.